tbuckley/cabot-search huggingface dataset:
Androgen Signaling Contributes to Sex Differences in Cancer by Inhibiting NF-κB Activation in T Cells and Suppressing Antitumor Immunity
Authors: Xiaomin Zhang, Limin Cheng, Chengqi Gao, Jing Chen, Shuangye Liao, Yongqiang Zheng, Liping Xu, Jingjing He, Danyang Wang, Ziqian Fang, Jianeng Zhang, Min Yan, Yi Luan, Siyu Chen, Likun Chen, Xiaojun Xia, Chunhao Deng, Guokai Chen, Wende Li, Zexian Liu, Penghui Zhou
Journal: Cancer Research (2023)

Sex is known to be an important factor in the incidence, progression, and outcome of cancer. A better understanding of the underlying mechanisms could help improve cancer prevention and treatment. Here, we demonstrated a crucial role of antitumor immunity in the sex differences in cancer. Consistent with observations in human cancers, male mice showed accelerated tumor progression compared with females, but these differences were not observed in immunodeficient mice. Androgen signaling suppressed T-cell immunity against cancer in males. Mechanistically, androgen-activated androgen receptor upregulated expression of USP18, which inhibited TAK1 phosphorylation and the subsequent activation of NF-κB in antitumor T cells. Reduction of testosterone synthesis by surgical castration or using the small-molecular inhibitor abiraterone significantly enhanced the antitumor activity of T cells in male mice and improved the efficacy of anti-PD-1 immunotherapy. Together, this study revealed a novel mechanism contributing to sex differences in cancer. These results indicate that inhibition of androgen signaling is a promising approach to improve the efficacy of immunotherapy in males.Androgen signaling induces immunosuppression in cancer by blocking T-cell activity through upregulation of USP18 and subsequent inhibition of NF-κB activity, providing a targetable axis to improve antitumor immunity in males.
The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression
Authors: Yun-Guang Hong, Zhigang Yang, Yan Chen, Tian Liu, Yuyuan Zheng, Chun Zhou, Guo-Cai Wu, Yinhui Chen, Juan Xia, Ruiting Wen, Wenxin Liu, Yi Zhao, Jin Chen, Xiangwei Gao, Zhanghui Chen
Journal: Cancer Research (2023)

Abstract N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myelogenous leukemia (AML). Identification of the key regulators of m6A modifications in AML could provide further insights into AML biology and uncover more effective therapeutic strategies for patients with AML. Here, we report overexpression of YTHDF1, an m6A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Whereas YTHDF1 was dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuated self-renewal, proliferation, and leukemic capacity of primary human and mouse AML cells in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of cyclin E2 in an m6A-dependent manner. Structure-based virtual screening of FDA-approved drugs identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocked the direct binding of YTHDF1 with m6A-modified mRNAs and inhibited YTHDF1-regulated cyclin E2 translation. Moreover, tegaserod reduced the viability of patient-derived AML cells in vitro and prolonged survival in patient-derived xenograft models. Together, our study defines YTHDF1 as an integral regulator of AML progression by regulating the expression of m6A-modified mRNAs, which might serve as a potential therapeutic target for AML. Significance: The m6A reader YTHDF1 is required for progression of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth.
Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases
Authors: Yiheng Chen, Tianyuan Lu, Ulrika Pettersson-Kymmer, Isobel D. Stewart, Guillaume Butler-Laporte, Tomoko Nakanishi, Agustin Cerani, Kevin Y. H. Liang, Satoshi Yoshiji, Julian Daniel Sunday Willett, Chen-Yang Su, Parminder Raina, Celia M. T. Greenwood, Yossi Farjoun, Vincenzo Forgetta, Claudia Langenberg, Sirui Zhou, Claes Ohlsson, J. Brent Richards
Journal: Nature Genetics (2023)
TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis
Authors: Kai Zhang, Yang Wang, Shiyu Chen, Jiali Mao, Yue Jin, Hui Ye, Yan Zhang, Xiwang Liu, Chenchen Gong, Xuejun Cheng, Xiaoli Huang, Andreas Hoeft, Qixing Chen, Xuekun Li, Xiangming Fang
Journal: Nature Metabolism (2023)

Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163+RETNLA+ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2hi). TREM2hi Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could serve as a therapeutic strategy for SICM.
Comment on: Intrapulmonary shunt and alveolar dead space in a cohort of patients with acute COVID-19 pneumonitis and early recovery
Authors: Maximilian Ackermann, Paul Tafforeau, Joseph Brunet, Jan C. Kamp, Christopher Werlein, Mark P. Kühnel, Joseph Jacob, Claire L. Walsh, Peter D. Lee, Tobias Welte, Danny D. Jonigk
Journal: European Respiratory Journal (2023)

<b>A compelling explanation for mosaic-like micro-ischaemia in the severe pathology of COVID-19 pneumonitis, which reflects the vasculopathy affecting the secondary lobule and the interlobular septae</b>http://bit.ly/3GwMkII
Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model
Authors: Jayanth S Shankara Narayanan, Tomoko Hayashi, Suna Erdem, Sara McArdle, Herve Tiriac, Partha Ray, Minya Pu, Zbigniew Mikulski, Aaron Miller, Karen Messer, Dennis Carson, Stephen Schoenberger, Rebekah R White
Journal: Journal for ImmunoTherapy of Cancer (2023)

Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity. Here, we aim to generate meaningful therapeutic immune effects by combining IRE with local (intratumoral) delivery of a CD40 agonistic antibody (CD40Ab).KPC46 organoids were generated from a tumor-bearing male KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) mouse. Orthotopic tumors were established in the pancreatic tail of B6/129 F1J mice via laparotomy. Mice were randomized to treatment with either sham laparotomy, IRE alone, CD40Ab alone, or IRE followed immediately by CD40Ab injection. Metastatic disease and immune infiltration in the liver were analyzed 14 days postprocedure using flow cytometry and multiplex immunofluorescence imaging with spatial analysis. Candidate neoantigens were identified by mutanome profiling of tumor tissue for ex vivo functional analyses.The combination of IRE+CD40 Ab improved median survival to greater than 35 days, significantly longer than IRE (21 days) or CD40Ab (24 days) alone (p<0.01). CD40Ab decreased metastatic disease burden, with less disease in the combination group than in the sham group or IRE alone. Immunohistochemistry of liver metastases revealed a more than twofold higher infiltration of CD8+T cells in the IRE+CD40 Ab group than in any other group (p<0.01). Multiplex immunofluorescence imaging revealed a 4-6 fold increase in the density of CD80+CD11c+ activated dendritic cells (p<0.05), which were spatially distributed throughout the tumor unlike the sham group, where they were restricted to the periphery. In contrast, CD4+FoxP3+ T-regulatory cells (p<0.05) and Ly6G+myeloid derived cells (p<0.01) were reduced and restricted to the tumor periphery in the IRE+CD40 Ab group. T-cells from the IRE+CD40 Ab group recognized significantly more peptides representing candidate neoantigens than did T-cells from the IRE or untreated control groups.IRE can induce local tumor regression and neoantigen-specific immune responses. Addition of CD40Ab to IRE improved dendritic cell activation and neoantigen recognition, while generating a strong systemic antitumor T-cell response that inhibited metastatic disease progression.
Alternate-day dosing of pomalidomide in relapsed/ refractory multiple myeloma: a multicenter, single-arm phase 2 trial
Authors: Thilo Zander, Thomas Pabst, Sämi Schär, Stefan Aebi, Ulrich Mey, Urban Novak, Erika Lerch, Gaëlle Rhyner Agocs, Jeroen Goede, Zuzanna Maniecka, Stefanie Hayoz, Axel Rüfer, Christoph Renner, Christoph Driessen
Journal: Leukemia (2023)
Correction: Continuous Indexing of Fibrosis (CIF): improving the assessment and classification of MPN patients
Authors: Hosuk Ryou, Korsuk Sirinukunwattana, Alan Aberdeen, Gillian Grindstaff, Bernadette J. Stolz, Helen Byrne, Heather A. Harrington, Nikolaos Sousos, Anna L. Godfrey, Claire N. Harrison, Bethan Psaila, Adam J. Mead, Gabrielle Rees, Gareth D. H. Turner, Jens Rittscher, Daniel Royston
Journal: Leukemia (2023)
Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors
Authors: Charlotte Lemech, Keith Dredge, Darryn Bampton, Edward Hammond, Andrew Clouston, Nigel J Waterhouse, Amanda C Stanley, Lucie Leveque-El Mouttie, Grace M Chojnowski, Andrew Haydon, Nick Pavlakis, Matthew Burge, Michael P Brown, David Goldstein
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Pixatimod is a unique activator of the Toll-like Receptor 9 pathway. This phase I trial evaluated safety, efficacy and pharmacodynamics of pixatimod and PD-1 inhibitor nivolumab in immunologically cold cancers. Methods 3+3 dose escalation with microsatellite stable metastatic colorectal cancer (MSS mCRC) and metastatic pancreatic ductal adenocarcinoma (mPDAC) expansion cohorts. Participants received pixatimod once weekly as a 1-hour intravenous infusion plus nivolumab every 2 weeks. Objectives included assessment of safety, antitumor activity, pharmacodynamics, and pharmacokinetic profile. Results Fifty-eight participants started treatment. The maximum tolerated dose of pixatimod was 25 mg in combination with 240 mg nivolumab, which was used in the expansion phases of the study. Twenty-one grade 3–5 treatment-related adverse events were reported in 12 participants (21%); one participant receiving 50 mg pixatimod/nivolumab had a treatment-related grade 5 AE. The grade 3/4 rate in the MSS mCRC cohort (n=33) was 12%. There were no responders in the mPDAC cohort (n=18). In the MSS mCRC cohort, 25 participants were evaluable (initial postbaseline assessment scans &gt;6 weeks); of these, three participants had confirmed partial responses (PR) and eight had stable disease (SD) for at least 9 weeks. Clinical benefit (PR+SD) was associated with lower Pan-Immune-Inflammation Value and plasma IL-6 but increased IP-10 and IP-10/IL-8 ratio. In an MSS mCRC participant with PR as best response, increased infiltration of T cells, dendritic cells, and to a lesser extent NK cells, were evident 5 weeks post-treatment. Conclusions Pixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation. Trial registration number NCT05061017 .
Correction: Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6 - methyladenosine of Notch1
Authors: Chaohui Gu, Zhiyu Wang, Naichun Zhou, Guanru Li, Yiping Kou, Yang Luo, Yidi Wang, Jinjian Yang, Fengyan Tian
Journal: Molecular Cancer (2023)
Risk of second primary malignancies in patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019
Authors: Lina van der Straten, Mark-David Levin, Manette A. W. Dinnessen, Otto Visser, Eduardus F. M. Posthuma, Jeanette K. Doorduijn, Anton W. Langerak, Arnon P. Kater, Avinash G. Dinmohamed
Journal: Blood Cancer Journal (2023)

The longevity of patients with chronic lymphocytic leukemia (CLL) has improved progressively over the past decades, making it essential to understand long-term health outcomes, such as second primary malignancies (SPMs). Therefore, this nationwide, population-based study assessed the risk of SPM development in CLL patients diagnosed during 1989-2019 in the Netherlands compared to the expected number of malignancies in an age-, sex-, and period-matched group from the general Dutch population. In 24,815 CLL patients followed for 162,698.49 person-years, 4369 SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.63 (95% confidence interval [CI] 1.59-1.68). This elevated risk was observed for solid (SIR, 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond five years post-diagnosis (SIR, 1.70; 95% CI, 1.62-1.77), for male individuals (SIR, 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SIR, 1.92; 95% CI, 1.79-2.05). The risk of SPMs was higher in CLL patients who received anti-neoplastic therapy (SIR, 2.12; 95% CI, 1.96-2.28), as compared with those who did not (SIR, 1.58; 95% CI, 1.53-1.63). Routine surveillance activities and tailored interventions to counteract the increased morbidity and excess mortality associated with SPMs are essential for improving long-term outcomes in CLL patients.
The longevity-associated BPIFB4 gene supports cardiac function and vascularization in ageing cardiomyopathy
Authors: Monica Cattaneo, Antonio P Beltrami, Anita C Thomas, Gaia Spinetti, Valeria Vincenza Alvino, Elisa Avolio, Claudia Veneziano, Irene Giulia Rolle, Sandro Sponga, Elena Sangalli, Anna Maciag, Fabrizio Dal Piaz, Carmine Vecchione, Aishah Alenezi, Stephen Paisey, Annibale A Puca, Paolo Madeddu
Journal: Cardiovascular Research (2023)

Abstract Aims The ageing heart naturally incurs a progressive decline in function and perfusion that available treatments cannot halt. However, some exceptional individuals maintain good health until the very late stage of their life due to favourable gene–environment interaction. We have previously shown that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene enjoy prolonged health spans and lesser cardiovascular complications. Moreover, supplementation of LAV-BPIFB4 via an adeno-associated viral vector improves cardiovascular performance in limb ischaemia, atherosclerosis, and diabetes models. Here, we asked whether the LAV-BPIFB4 gene could address the unmet therapeutic need to delay the heart’s spontaneous ageing. Methods and results Immunohistological studies showed a remarkable reduction in vessel coverage by pericytes in failing hearts explanted from elderly patients. This defect was attenuated in patients carrying the homozygous LAV-BPIFB4 genotype. Moreover, pericytes isolated from older hearts showed low levels of BPIFB4, depressed pro-angiogenic activity, and loss of ribosome biogenesis. LAV-BPIFB4 supplementation restored pericyte function and pericyte-endothelial cell interactions through a mechanism involving the nucleolar protein nucleolin. Conversely, BPIFB4 silencing in normal pericytes mimed the heart failure pericytes. Finally, gene therapy with LAV-BPIFB4 prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in older mice by improving microvasculature density and pericyte coverage. Conclusions We report the success of the LAV-BPIFB4 gene/protein in improving homeostatic processes in the heart’s ageing. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people.
Advances in sequencing technologies for amyotrophic lateral sclerosis research
Authors: Evan Udine, Angita Jain, Marka van Blitterswijk
Journal: Molecular Neurodegeneration (2023)

Abstract Amyotrophic lateral sclerosis (ALS) is caused by upper and lower motor neuron loss and has a fairly rapid disease progression, leading to fatality in an average of 2-5 years after symptom onset. Numerous genes have been implicated in this disease; however, many cases remain unexplained. Several technologies are being used to identify regions of interest and investigate candidate genes. Initial approaches to detect ALS genes include, among others, linkage analysis, Sanger sequencing, and genome-wide association studies. More recently, next-generation sequencing methods, such as whole-exome and whole-genome sequencing, have been introduced. While those methods have been particularly useful in discovering new ALS-linked genes, methodological advances are becoming increasingly important, especially given the complex genetics of ALS. Novel sequencing technologies, like long-read sequencing, are beginning to be used to uncover the contribution of repeat expansions and other types of structural variation, which may help explain missing heritability in ALS. In this review, we discuss how popular and/or upcoming methods are being used to discover ALS genes, highlighting emerging long-read sequencing platforms and their role in aiding our understanding of this challenging disease.
Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study
Authors: Jennifer Smith, Loveleen Bansi-Matharu, Valentina Cambiano, Dobromir Dimitrov, Anna Bershteyn, David van de Vijver, Katharine Kripke, Paul Revill, Marie-Claude Boily, Gesine Meyer-Rath, Isaac Taramusi, Jens D Lundgren, Joep J van Oosterhout, Daniel Kuritzkes, Robin Schaefer, Mark J Siedner, Jonathan Schapiro, Sinead Delany-Moretlwe, Raphael J Landovitz, Charles Flexner, Michael Jordan, Francois Venter, Mopo Radebe, David Ripin, Sarah Jenkins, Danielle Resar, Carolyn Amole, Maryam Shahmanesh, Ravindra K Gupta, Elliot Raizes, Cheryl Johnson, Seth Inzaule, Robert Shafer, Mitchell Warren, Sarah Stansfield, Roger Paredes, Andrew N Phillips
Journal: The Lancet HIV (2023)
Metabolism in stem cell driven leukaemia: parallels between haematopoiesis and immunity
Authors: Kevin M. Rattigan, Martha M. Zarou, Vignir Helgason
Journal: Blood (2023)

Our understanding of cancer metabolism spans from its role in cellular energetics and supplying the building blocks necessary for proliferation, to maintaining cellular redox and regulating the cellular epigenome and transcriptome. Cancer metabolism, once thought to be solely driven by upregulated glycolysis, is now known to comprise multiple pathways with great plasticity in response to extrinsic challenges. Furthermore, cancer cells can modify their surrounding niche during disease initiation, maintenance, and metastasis, thereby contributing to therapy resistance. Leukemia is a paradigm model of stem cell-driven cancer. In this study, we review how leukemia remodels the niche and rewires its metabolism, with particular attention paid to therapy-resistant stem cells. Specifically, we aim to give a global, nonexhaustive overview of key metabolic pathways. By contrasting the metabolic rewiring required by myeloid-leukemic stem cells with that required for hematopoiesis and immune cell function, we highlight the metabolic features they share. This is a critical consideration when contemplating anticancer metabolic inhibitor options, especially in the context of anticancer immune therapies. Finally, we examine pathways that have not been studied in leukemia but are critical in solid cancers in the context of metastasis and interaction with new niches. These studies also offer detailed mechanisms that are yet to be investigated in leukemia. Given that cancer (and normal) cells can meet their energy requirements by not only upregulating metabolic pathways but also utilizing systemically available substrates, we aim to inform how interlinked these metabolic pathways are, both within leukemic cells and between cancer cells and their niche.
<i>CREBBP</i> Alterations are Associated with A Poor Prognosis in <i>de novo</i> AML
Authors: Adam J. Lamble, Kohei Hagiwara, Robert B Gerbing, Jenny L Smith, Pandurang Kolekar, Rhonda E Ries, Edward A Kolb, Todd Alonzo, Xiaotu Ma, Soheil Meshinchi
Journal: Blood (2023)
Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study
Authors: Indra A. Van Assche, Evangeline A. Huis in 't Veld, Kristel Van Calsteren, Mathilde van Gerwen, Jeroen Blommaert, Elyce Cardonick, Michael J. Halaska, Robert Fruscio, Monica Fumagalli, Jurgen Lemiere, Elisabeth M. van Dijk-Lokkart, Camilla Fontana, Harm van Tinteren, Jessie De Ridder, Martine van Grotel, Marry M. van den Heuvel-Eibrink, Lieven Lagae, Frédéric Amant
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. This multicenter cohort study reports on the long-term effects of prenatal exposure to maternal cancer and its treatment on cognitive and behavioral outcomes in 9-year-old children. In total, 151 children (mean age, 9.3 years; range, 7.8-10.6 years) were assessed using a neurocognitive test battery and parent-report behavioral questionnaires. During pregnancy, 109 children (72.2%) were exposed to chemotherapy (only or in combination with other treatment modalities), 18 (11.9%) to surgery only, 16 (10.6%) to radiotherapy, one to trastuzumab, and 16 (10.6%) were not exposed to oncologic treatment. Mean cognitive and behavioral outcomes were within normal ranges. Gestational age at birth showed a positive association with Full Scale Intelligence Quotient (FSIQ), with the average FSIQ score increasing by 1.6 points for each week increase in gestational age (95% CI, 0.7 to 2.5; P &lt; .001). No difference in FSIQ was found between treatment types (F[4,140] = 0.45, P = .776). In children prenatally exposed to chemotherapy, no associations were found between FSIQ and chemotherapeutic agent, exposure level, or timing during pregnancy. These results indicate a reassuring follow-up during the critical maturational period of late childhood, when complex functions develop and rely on the integrity of early brain development. However, associations were observed with preterm birth, maternal death, and maternal education.